Substituted 3-aminosydnonimines

ABSTRACT

Substituted 3-aminosydnonimines of the formula I ##STR1## and pharmacologically acceptable acid addition salts thereof, in which R 1  denotes hydrogen or the radical --COR 4 , 
     R 2  denotes alkyl or phenyl alkyl having 1 to 4 C atoms in the alkyl group, 
     R 4  denotes, for example, an aryl radical, and processes and formulations for controlling or preventing cardiovascular diseases by administering an effective amount of such compounds to a host in need thereof.

This is a continuation of application Ser. No. 07/598,037 filed on Oct.16, 1990, now abandoned, which is a continuation of Ser. No. 07/290,615filed Dec. 27, 1988, now abandoned.

The invention relates to pharmacologically active substituted3-aminosydnonimines of the general formula I ##STR2## and to thepharmacologically acceptable acid addition salts thereof, in which

A denotes the radical --CH₂ --, --O--, --S(O_(n))--, --N(R³)-- or adirect bond,

R¹ denotes hydrogen, nitroso (--NO) or the radical --COR⁴,

R² and R³ denote alkyl having 1 to 4 C atoms or phenylalkyl having 1 to4 C atoms in the alkyl radical,

R⁴ denotes an aliphatic radical which has 1 to 6 C atoms and can also besubstituted by alkoxy having 1 to 6 C atoms or by an aliphatic thioradical having up to 4 C atoms; a cycloaliphatic radical having 5 to 7 Catoms; a bicycloaliphatic radical having 7 to 14 C atoms; atricycloaliphatic radical having 7 to 16 C atoms; an alkoxy radicalwhich has 1 to 18 C atoms and can also be substituted by alkoxy having 1to 6 C atoms; an aryloxy radical having 6 to 10 C atoms; analkoxycarbonyl radical having a total of 2 to 7 C atoms; an aryl radicalhaving 6 to 10 C atoms; an aryl radical which has 6 to 10 C atoms and ismono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkylradicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to4 C atoms and/or 1 or 2 nitro groups and/or 1 or 2 hydroxyl groupsand/or 1 or 2 nitro groups and/or 1 or 2 hydroxyl groups and/or 1 or 2alkylcarbonyloxy radicals having 1 to 4 C atoms, and/or 1 to 3 alkylthioradicals having 1 to 4 C atoms and/or a trifluoromethyl radical and/oran imidazole radical; imidazolyl; pyridyl; thienyl; styryle; n denotesthe number 0, 1 or 2.

The invention furthermore relates to a process for the preparation ofthe compounds I according to the invention and to the use thereof.

If A denotes one of the radicals --CH₂ --, --O--, --S(O_(n))-- or--N(R³)-- there is in the 3-position of the sydnonimine the radical of aheterocyclic 6-membered ring which has one hetero atom (N) or which hastwo hetero atoms (N, O or N,S or N,N) and which is substituted in thestated manner. If A denotes a direct bond there is in the 3-position ofthe sydnonimine a pyrrolidine radical which is disubstituted in the2,5-positions.

Aliphatic radicals, thio radicals, alkyl radicals and alkoxy radicalscan be straight-chain or branched. This also applies when they occur assubstituents of other radicals, for example as substituents of arylradicals, or in conjunction with other radicals, for example asphenalkyl, as alkoxycarbonyl, as alkylcarbonyloxy or as alkoxyalkoxy.

Preferred for A are the direct bond and the bivalent radicals: --CH₂ --,--O--, and --S(O₂)--, of which the radical --CH₂ -- is particularlypreferred.

The alkyl or phenalkyl radicals representing R² and R³ can be identicalor different. The radicals R² are preferably in cis-position relative toone another.

Examples of suitable phenalkyl radicals representing R² and/or R³ arebenzyl, 2-phenethyl, 3-phenylpropyl and 3-phenyl-butyl. Examples ofsuitable alkyl radicals representing R² and/or R³ are methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl and tert.-butyl. Methyl ispreferred for R² and/or R³.

Particularly suitable aliphatic radicals representing R⁴ are alkylradicals, preferably having 1 to 4 C atoms. The aliphatic radicals,especially alkyl radicals, representing R⁴ can also be substituted byalkoxy having 1 to 6 C atoms, in particular 1 to 4 C atoms, preferably 1to 3 C atoms. Examples of alkyl and alkoxyalkyl radicals which canrepresent R⁴ are: methyl; ethyl; n-propyl; i-propyl, n-, i-, sec.- andtert.-butyl; n- and i-pentyl; n- and i-hexyl; methoxy-, ethoxy-,n-propoxy-, i-propoxy-, n-butoxy-, i-butoxy-methyl; 2-methoxy-,2-ethoxy-, 2-n-propoxy-, 2-i-propoxy-, 2-n-butoxy-ethyl; 2-methoxy-,3-ethoxy-, 3-n-propoxy-, 3-i-propoxy-propyl or -i-propyl. The aliphaticradicals, especially the alkyl radicals, representing R⁴ can also besubstituted by an aliphatically substituted thio radical having up to 4C atoms. Examples of such aliphatic thio radicals are alkylthio radicalshaving 1 to 4 C atoms, such as, for example, methyl-, ethyl-, n-propyl-,i-propyl-, n-butyl- and tert.-butyl-thio, but preferably allylthio (CH₂═CH--CH₂ --S--). Particularly suitable cycloalphatic radicalsrepresenting R⁴ are cycloalkyl radicals having 5 to 7 C atoms, inparticular cyclopentyl, and preferably cyclohexyl. An especiallysuitable bicycloaliphatic radical representing R⁴ is2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl (=3-pinanyl). An especiallysuitable tricycloaliphatic radical representing R⁴ istricyclo[3.3.1.1³,7 ]decan-1-yl (=1-adamantyl).

The alkoxy substituents for the alkoxy radicals have, in particular, 1to 4 C atoms. Examples of alkoxy radicals and alkoxyalkoxy radicalswhich can represent R⁴ are: methoxy; ethoxy; n- and i-propoxy; n-, i-,sec.- and tert.-butoxy; n-pentyloxy; i-hexyloxy; n-octyloxy;n-docecyloxy; n-hexadecyloxy; n-heptadecyloxy; n-octadecyloxy; methoxy-,ethoxy-, n-propoxy-, i-propoxy-, n-butoxy-methoxy; 2-methoxy-,2-ethoxy-, 2-n-propoxy-, 2-i-propoxy-ethoxy; 3-methoxy-, 3-ethoxy-,3-n-propoxy-, 3-i-propoxy-propoxy; 4-methoxy-, 4-ethoxy-, 4-n-propoxy-,3-propoxy-, 4-n-butoxy-butoxy.

The alkoxycarbonyl radical representing R⁴ preferably has 2 to 5 Catoms. Examples which may be mentioned for this are: methoxy-, ethoxy-,n-propoxy-, i-propoxy-, n-butoxy- and i-butoxy-carbonyl. Theethoxycarbonyl radical is particularly suitable as alkoxycarbonylradical representing R⁴.

Examples of substituted and unsubstituted aryl radicals to be mentionedas representing R⁴ are α- or β-naphthyl radicals, but especially thephenyl radical. Examples of aryloxy radicals to be mentioned asrepresenting R⁴ are α- or β-naphthoxy radicals, but especially thephenoxy radical. The aryl radicals representing R⁴ can be mono-, di- ortrisubstituted, but even with trisubstitution only a maximum of 2 nitrogroups can be present, such as, for example, 2-methyl-4,6-dinitrophenyland 2-chloro-6-methyl-4-nitrophenyl. In the case of voluminoussubstituents only a disubstitution or monosubstitution of nitro groupsmay be possible. Examples of suitable halogen substituents for the arylradicals are fluorine, chlorine and/or bromine atoms. Examples ofalkylcarbonyloxy substituents to be mentioned for the aryl radicals,especially for a phenyl radical, are: acetoxy, propionyloxy,n-butyryloxy and i-butyryloxy.

Examples of optionally substituted aryl radicals representing R⁴ are:phenyl, 2-, 3- or 4-methyl-, -ethyl-, -n-propyl-, -i-propyl-phenyl; 2-,3- or 4-methoxy-, -ethoxy-, -n-propoxy-, -i-propoxyphenyl; 2-, 3- or4-fluoro-, -chloro- or -bromo-phenyl; 2-, 3- or 4-nitrophenyl; 2-, 3-or4-hydroxyphenyl; 2-, 3- or 4-acetoxy-, -propionyloxy-,-n-butyryloxy-phenyl; 2,3-, 2,4-, 2,5- or 2,6-dimethyl-, -diethyl-,-dipropyl-phenyl; 2- or 3-methyl-4-chlorophenyl; 2-or3-ethyl-4-fluorophenyl; 2-chloro-4-ethylphenyl;2-bromo-4-i-propylphenyl; 2,6-diethoxy-4-chlorophenyl; 2,3,4-, 3,4,5- or2,3,5-trimethyl-, -triethyl-, -tripropyl-, -trimethoxy-, -triethoxy- or-tripropoxy-phenyl; 2-hydroxy-3-, -4- or -5-chlorophenyl; 2-methyl-3-,-4- or -4-acetoxyphenyl.

Substituted aryl radicals to be particularly mentioned as representingR⁴ are: methylphenyl (=tolyl), methoxyphenyl and chlorophenyl. Theimdazolyl radical representing R⁴ is preferably a 1-imidazolyl radical.

The following are preferred for R⁴ : methyl, ethyl, cyclohexyl, phenyl,4-chlorophenyl, 4-methoxyphenyl, methoxy, ethoxy, n-propoxy, i-propoxy,n-decyloxy, n-octadecyloxy, 2-n-propoxy-ethoxy, 2-i-propoxy-ethoxy,n-butoxymethyl, 2-n-butoxy-ethoxy and allylthiomethyl.

n is preferably the number 2.

Preferred compounds of the formula I are those in which A denotes adirect bond, --CH₂ -- or --S(O₂)--, R² denotes methyl, and R¹ denoteshydrogen, --NO or --COR⁴ with R⁴ =methyl, ethyl, methoxy, ethoxy, n- andi-propoxy, phenyl, cyclohexyl, allylthiomethyl, n-butoxymethyl or2-n-butoxy-ethoxy.

A compound of the general formula I can be prepared in such a way that acompound of the general formula II ##STR3## in which A and R² having themeanings already mentioned, is cyclized to give a compound of thegeneral formula Ia ##STR4## and that the latter, or an acid additionsalt thereof, is, for the case where a compound of the formula I with R¹=--COR⁴ is to be prepared, acylated with an acylating agent whichintroduces the radical --COR⁴, or is, for the case where a compound ofthe formula I with R¹ =--NO is to be prepared, nitrosated, and theresulting compound is, where appropriate, converted into apharmacologically acceptable acid addition salt.

The cyclization of the compound II to give the compound Ia is carriedout in a suitable organic or inorganic solvent, dispersant or diluentwith the addition of a cyclizing agent, normally at temperatures from-10° to 40° C., in particular 0° to 40° C., preferably at 0° to 20° C.

Suitable cyclizing agents are those which set up a pH of 3or below inaqueous solution, that is to say, for example, strong acids such asmineral acids, such as sulphuric, nitric or phosphoric acid, preferablyhydrogen chloride, or else strong organic acids such as sulphonic acidsor trifluoroacetic acid. The cyclization is normally carried out whilecooling in ice. 0.1 to 10 mol, preferably 1 to 5 mol, of the cyclizingagent is used, for example, based on 1 mol of the compound of theformula II. The cyclizing agent is normally used in excess. It isparticularly convenient to use hydrogen chloride as cyclizing agent,which is normally passed into the reaction mixture to saturation.Normally obtained in the cyclization is the corresponding acid additionsalt of the compound Ia.

Examples of suitable solvents, dispersants or diluents are: alcohols,for example those having 1 to 8 C atoms, especially those having 1 to 6C atoms, preferably those having 1 to 4 C atoms, such as, for example,methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-,sec-, tert-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, isooctylalcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (mixture),benzyl alcohol; ethers, especially those having 2 to 8 C atoms in themolecule, such as, for example, diethyl ether, methyl ethyl ether,di-n-propyl ether, di-isopropyl ether, methyl n-butyl ether, methyltert-butyl ether, ethyl propyl ether, di-butyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, bis-β-methoxyethyl ether;oligoethylene glycol dimethyl ethers such as, for example, tetraglyme orpentaglyme; alkyl carboxylates, especially those having 2 to 10 C atomsin the molecule, such as, for example, methyl, ethyl, butyl or isobutylformate, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or secbutyl,amyl, isoamyl, hexyl, cyclohexyl or benzyl acetate, methyl, ethyl orbutyl propionate; ketones, especially those having 3 to 10 C atoms inthe molecule, such as, for example, acetone, methyl ethyl ketone, methyln-propyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, di-n-propylketone, di-iso-propyl ketone, di-iso-butyl ketone, cyclopentanone,cyclohexanone, methylcyclohexanone, dimethylcyclohexanone, benzophenone,acetophenone; aliphatic hydrocarbons such as, for example, hexane,heptane, low- and high-boiling petroleum ethers, special grades ofpetroleum spirit, and white spirit; cycloaliphatic hydrocarbons such as,for example, cyclopentane, cyclohexane, methylcyclohexane, tetralin,decalin; aromatic hydrocarbons such as, for example, benzene, toluene,o-, m- and p-xylene, ethylbenzene; halogenated aliphatic or aromatichydrocarbons such as, for example, methylene chloride, chloroform,carbon tetrachloride, 1,2-dichloroethane, chlorobenzene,dichlorobenzene; hexamethylphosphoric triamide; sulphoxides such as, forexample, dimethyl sulphoxide; tetramethylene sulphone; water. It is alsopossible to use mixtures of various solvents or dispersants, for examplewater/methanol or, preferably, ethyl acetate/methanol.

The compounds of the formula IA represent compounds of the generalformula I according to the invention for the case where R¹ is hydrogen.

The acylation of the compound of the formula Ia, which can also be inthe form of an acid addition salt, to introduce the radical R¹ =--COR⁴can be carried out in a manner known per se using a suitable acylatingagent of the formula III ##STR5## in which X represents a radical whichcan be eliminated nucleophilically. Examples of meanings of X in theformula III are, in particular, halogen, preferably --Cl or --Br; --OH;--O--alkyl, in particular having 1 to 5 C atoms; --O-- aryl, where thearyl radical is, in particular, a phenyl radical which can also besubstituted one or more times by alkyl, in particular methyl, and/ornitro, and is, for example, a tolyl or dinitrophenyl or nitrophenylradical; --O--CO--R⁴, --O--CO--O-alkyl, in particular having 1 to 5 Catoms in the alkyl radical, or the radical of an azole or benzazolewhich has at least 2 N atoms in the quasiaromatic 5-membered ring and isbonded via one N atom.

The acylation is expediently carried out in liquid phase in the presenceof an inert solvent, dispersant or diluent or in an excess of theacylating agent, expediently while stirring.

The molar ratio between the compound of the formula Ia and the acylatingagent of the formula III in the acylation is theoretically 1:1. It isexpedient to use the acylating agent of the formula III in a slightmolar excess. Excesses of up to 30 mol-% are adequate as a rule, that isto say the molar ratio between the compound of the formula Ia and theacylating agent of the formula III is normally 1:(1 to 1.3), preferably1:(1 to 1.2). If an acid is eliminated in the acylation reaction, it isexpedient to add an acid trap, such as, for example, an alkali metalhydroxide such as, for example, sodium, potassium or lithium hydroxide,a tertiary organic amine such as, for example, pyridine ortriethylamine, an alkali metal carbonate or alkali metal bicarbonatesuch as, for example, sodium carbonate or sodium bicarbonate, or analkali metal salt of a weak organic acid such as, for example, sodiumacetate. It is also possible to add suitable catalysts in the acylationreaction, such as, for example, 4-dimethylaminopyridine.

The acylation can be carried out in principle at temperatures between-10° C. and the boiling point of the solvent, dispersant or diluentused. In many cases the reaction is carried out at 0° to 50° C., inparticular at 0° to 30° C. and, preferably, at room temperature.

The compounds of the formula III are acylating agents and thusrepresent, for example: for X=halogen acid halides or halogenoformicesters, of which acid chlorides and chloroformic esters are preferred;for --OH carboxylic acids; for --O-alkyl and --O-aryl esters, of whichthe tolyl, 2,4-dinitro- or 4-nitrophenyl esters are preferred; for--O--CO--R⁴ anhydrides, for --O--CO--O-alkyl mixed carboxylic carbonicanhydrides; or heterocyclic amides or azolides, especially ofN,N'-carbonyldiazoles such as, for example, N,N'-carbonyldiimidazole,2,2'-carbonyldi-1,2,3-triazole, 1,1'-carbonyldi-1,2,4-triazole,N,N'-carbonyldipyrazole, and 2,2'-carbonylditriazole (compare, forexample, H. A. Staab, M. Lucking and F. H. Durr, Chem. Ber. 95, (1962),1275 et seq., H. A. Staab and A. Mannschreck, Chem. Ber. 95, (1962),1284 et seq.; H. A. Staab and W. Rohr, "Synthesen mit heterocyclischenAmiden (Azoliden)" (Syntheses with heterocyclic amides (azolides)) in"Neuere Methoden der Praparativen Organischen Chemie" (New Methods ofPreparative Organic Chemistry), volume V, Verlag Chemie, 1967, pages 53et seq., especially pages 65 to 69). The acylating agents of the formulaIII can be prepared by processes known per se.

When a carboxylic acid is used as acylating agent, it is expedient toadd an activating agent which has the task of increasing or activatingthe acylating power of the carboxylic acid, or of converting thecarboxylic acid in situ or, preferably, shortly before the reaction withthe compound of the formula Ia into a reactive carboxylic acidderivative of the formula III. Examples of suitable activating agents ofthis type are: N,N'-disubstituted carbodiimides, especially when theycontain at least one secondary or tertiary alkyl radical, such as, forexample, diisopropyl, dicyclohexyl- orN-methyl-N'-tert.-butylcarbodiimide (compare Methodicum Chimicum, VerlagG. Thieme, Stuttgart, vol. 6, (1974), page 682/683, and Houben-Weyl,Methoden der Org. Chemie (Methods of Organic Chemistry), vol. 8, (1952),page 521/522); carbonic acid derivatives such as, for example, phosgene,chloroformic esters, especially having 1 to 5 C atoms in the alkylradical (compare, for example, Tetrahedron Letters 24 (1983), 3365 to3368); carbonic esters such as, for example, di-N-succinimidylcarbonate, diphthalimidyl carbonate,1,1'-(carbonyldioxy)-dibenzotriazole or di-2-pyridyl carbonate (compare,for example, Tetrahedron Letters, vol. 25, No. 43, 4943-4946), whereappropriate in the presence of suitable catalysts such as, for example,4-dimethylaminopyridine. Also suitable as activating agents areN,N'-carbonyldiazoles such as, for example, N,N'-carbonyl-diimidazole,2,2'-carbonyldi-1,2,3-triazole, 1,1'-carbonyldi-1,2,4-triazole,N,N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditetrazole,N,N'-carbonyl-dibenzimidazole or N,N'-carbonyldibenzotriazole (compare,for example, H. A. Staab, M. Lucking and F. H. Durr, loc. cit.; H. A.Staab and A. Mannschreck, loc. cit.; H. A. Staab and W. Rohr loc. cit.).Commercially available N,N'-carbonyldiimidazole is often used asN,N'-carbonyl-diazole. The other N,N'-carbonyldiazoles can, however,also be obtained easily from the relevant azole and phosgene.

Also suitable as activating agents for carboxylic acids are: derivativesof oxalic acid such as, for example, oxalyl chloride (compare, forexample, GB Patent 2,139,225) or N,N'-oxalyl-diazoles such as, forexample, 1,1'-oxalyl-di-imidazole, 1,1'-oxalyldi-1,2,4-triazole and1,1'-oxalyl-di-1,2,3,4-tetrazole (cf. for example, Shizuaka Murata,Bull. Chem. Soc. Jap. 57, 3597-3598 (1984)); methylethylphosphinicanhydride (compare, for example, German Offenlegungsschrift 3,101,427);diphosphorus tetraiodide (Chem. Lett. 1983, 449); dialkyl disulphite(Indian J. Chem. 21, 259 (1982)); or other reactive agents.

Examples of suitable solvents, dispersants or diluents for the acylationare those which have been mentioned for carrying out the cyclization,and in addition, for example, pyridine and amides, such as, for example,dimethylformamide. Besides water, preferred for the acylation are polarorganic solvents such as dimethylformamide, dimethyl sulphoxide orpyridine. Also suitable are solvent mixtures such as, for example, amixture of water and methylene chloride.

If a compound of the formula I with R¹ =--NO is to be prepared, acompound of the formula Ia, which can also be in the form of an acidaddition salt, is nitrosated in a manner known per se, expediently in asuitable inert solvent or a solvent mixture, preferably in water,normally at temperatures from 0° to 40° C., and preferably attemperatures from 0° to 10° C. The nitrosation is carried out, forexample, with nitrous acid, NO, NOCl or NO-containing gas mixtures. Thenitrosation is expediently carried out with nitrous acid, which isadvantageously generated from an alkali metal nitrite, for examplesodium nitrite, and an acid, especially hydrochloric acid. It isexpedient to adjust the aqueous solution of the compound Ia to a pH of 1to 3 with an acid, especially hydrochloric acid, and to add the alkalimetal nitrite in the form of an aqueous solution dropwise to the stirredand cooled solution of the compound.

The compounds of the formula I according to the invention can exist invarious configurations in cis or in trans form, it being possible forthe trans forms to be racemic mixtures or in optically active form. Toprepare these various isomers it is possible to use processes known perse, such as selective synthesis, chiral synthesis or separation ofracemic mixtures by known methods.

The substituted 3-aminosydnonimines of the general formula I form acidaddition salts with inorganic or organic acids. Suitable to form suchacid addition salts are inorganic or organic acids. Examples of suitableacids are hydrogen chloride, hydrogen bromide, phosphoric, nitric,sulphuric, oxalic, lactic, tartaric, acetic, salicyclic, benzoic,formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic,fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic,isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipicacid or naphthalendisulphonic acids, in particularnaphthalene-1,5-disulphonic acid. Pharmacologically acceptable acidaddition salts are preferred. The acid addition salts can be prepared ascustomary by mixing the components, expediently in suitable solvent ordiluent. The acid addition salts are produced in the synthesis of thecompounds of the formula Ia.

The required starting compounds of the general formula II can beprepared in a manner known per se by Strecker's amino nitrile synthesisfrom compounds of the general formula IV ##STR6## in which A and R² havethe abovementioned meanings, by reaction with formaldehyde andhydrocyanic acid or sodium cyanide in a suitable solvent, for examplewater, the initial result being a compound of the general formula V##STR7## which is converted by nitrosation into the compound II. Thenitrosation is carried out in a known manner, expediently in a suitableinert solvent or solvent mixture, preferably in water, normally attemperatures from 0° to 40° C. and preferably at temperatures from 0° to10° C. The nitrosation is carried out, for example, with nitrous acid,NO, NOCl or NO-containing gas mixtures. The nitrosation is expedientlycarried out with nitrous acid, which is advantageously generated from analkali metal nitrite, for example sodium nitrite, and an acid,especially hydrochloric acid. It is expedient to adjust the aqueoussolution of the compound V to a pH of 1 to 3 with an acid, especiallyhydrochloric acid, and to add the alkali metal nitrite in the form of anaqueous solution dropwise to the stirred and cooled solution of thecompound.

The compound II can be isolated from the solution of the compound lIobtained in this way, or the solution of the compound II can besubjected directly to the cyclization reaction. However, it is normallyappropriate for the subsequent cyclization to take up the nitrosocompound II initially in a suitable organic solvent, and to carry outthe cyclization to give the compound of the formula Ia in it, whereappropriate after addition of another solvent.

Some of the compounds of the general formula IV are known (compare, forexample, C. G. Overberger et al., J. Amer. Chem. Soc. 77, (1955) 4100),or they can be prepared, starting from compounds of the general formulaVI ##STR8## either by a) nitrosating a compound of the formula VI togive the N-nitroso compound VlI, and then reducing, expediently withlithium aluminium hydride; ##STR9## or by, in a manner known per se, b)converting a compound of the formula VI with potassium cyanate in acidmedium into the urea derivative VIII, which is then converted byoxidation with sodium hypochlorite by Hoffman degradation into thecompound IV: ##STR10##

Starting compounds of the formula VI are known (compare, for example,Backer, Van der Ley, Rec. Trav. Chim. Pays-Bas 70, (1951) 564; Berlin,Sytschewa, Z. obsc. Chim. 20, (1950) 640; Idson, Spoerri, J. Amer. Chem.Soc. 76, (1954) 2902) or can be prepared by the processes known forthese classes of compounds. Thus, compounds of the formula VI can beprepared, by ring closure with ammonia, for example from compounds ofthe general formula IX

    R.sup.2* ═CH--CH.sub.2 --A--CH.sub.2 --CH═R.sup.2* (IX)

in which A denotes --SO-- or --S(O₂)-- and R^(2*) denotes a radicalwhich is converted on reaction with ammonia, by addition of hydrogen,into the abovementioned radical R², which compounds can be prepared bymethods known per se. The reaction with ammonia can be carried out attemperatures from 20° to 150° C., preferably at 60° to 100° C., with orwithout solvent.

If the reaction of the compounds of the formula IX is carried out notwith ammonia but with hydrazine under the abovementioned conditions, itis possible to obtain compounds of the formula IV directly in the ringclosure.

The compounds of the general formula I and the pharmacologicallyacceptable acid addition salts thereof have valuable pharmacologicalproperties. Their action on the cardiovascular system is particularlypronounced. Compared with known sydnonimine compounds substituted in the3-position, for example those of EP-B 59,356, as well as thecommercially available compound of similar structure, molsidomine, theyhave, for example, surprisingly a considerably longer duraction ofaction. For example, they lower the blood pressure as well as thepulmonary artery pressure and the left ventricular end-diastolicpressure and thus contribute to relieving the action of the heart in thesense of an antianginal action, without thereby provoking a reflextachycardia.

The compounds of the formula I and the pharmacologically acceptable acidaddition salts thereof can thus be administered to humans as medicinesalone, in mixtures with one another or in the form of pharmaceuticalcompositions which allow enteral or parenteral use and which contain asactive ingredient an effective dose of at least one compound of theformula I, or of an acid addition salt thereof, besides customarypharmaceutically acceptable vehicles and additives.

The medicines can be administered orally, for example in the form ofpills, tablets, lacquered tablets, sugar-coated tablets, hard and softgelatin capsules, solutions, syrups, emulsions or suspensions, oraerosol mixtures. However, administration can also take place rectally,for example in the form of suppositories, or parenterally, for examplein the form of injectable solutions, or percutaneously, for example inthe form of ointments or tinctures. The pharmaceutical products containthe active compound of formula I or pharmaceutically-acceptableacid-addition salts thereof from about 0.5 to 90 percent by weight.

To prepare the pharmaceutical products it is possible to usepharmaceutically inert inorganic or organic vehicles. Examples which canbe used for the preparation of pills, tablets, sugar-coated tablets andhard gelatin capsules are lactose, maize starch or derivatives thereof,talc, stearic acid or salts thereof etc. Examples of vehicles for softgelatin capsules and suppositories are fats, waxes, semisolid and liquidpolyols, natural or hardened oils etc. Examples of suitable vehicles forthe preparation of solutions and syrups are water, sucrose, invertsugar, glucose, polyols etc. Examples of suitable vehicles for thepreparation of injectable solutions are water, alcohols, glycerol,polyols or vegetable oils.

The pharmaceutical products can, besides the active substances andvehicles, additionally contain additives such as, for example, fillers,extenders, disintegrants, binders, lubricants, wetting agents,stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavourings or aromatizing agents, buffer substances, as well assolvents or solubilizers or agents to achieve a depot effect, and saltsto alter the osmotic pressure, coating agents or antioxidants. They canalso contain two or more compounds of the formula I or pharmacologicallyacceptable acid addition salts thereof, and other therapeutically activesubstances too.

Examples of such other therapeutically active substances are: β-receptorblockers such as, for example, propranolol, pindolol and metoprolol;vasodilators such as, for example, carbocromen; sedatives such as, forexample, barbituric acid derivatives, 1,4-benzodiazepines andmeprobamate; diuretics such as, for example, chlorothiazide; cardiotonicagents such as, for example, digitalis products; agents to lower bloodpressure such as, for example, hydralazine, dihydralazine, prazosin,clonidine, Rauwolfia alkaloids; agents which lower the blood level offatty acids such as, for example, bezafibrate, fenofibrate; agents forthe prophylaxis of thrombosis such as, for example, phenprocoumon,additionally N-substituted N-nitroso-aminoacetonitriles of the formulaII, where A and R² have the meanings mentioned, and where A denotes, inparticular, --CH₂ --, S(O₂)--, --O-- or a direct bond, and/or R² denotesmethyl. The N-substituted N-nitroso-aminoacetonitriles of the formula IIhave similarly beneficial pharmacological properties as the compounds ofthe formula I.

The compounds of the formula I, the pharmacologically acceptable acidaddition salts thereof and pharmaceutical products which containcompounds of the formula I or pharmacologically acceptable acid additionsalts thereof as active substances can be used in humans to control orprevent diseases of the cardiovascular system, for example asantihypertensive medicines for the various types of high blood pressure,to control or prevent angina pectoris etc. The dosage can vary withinwide limits and should be adjusted in each individual case to suit theindividual circumstances. In general, an appropriate daily dose on oraladministration is about 0.5 to 100 mg, preferably 1 to 20 mg, perindividual person. With other modes of administration too, because ofthe good absorption of the active substances the daily dose is insimilar ranges of amounts, that is to say in general likewise 0.5 to 100mg/person. The daily dose is normally divided into several, for example2 to 4, partial administrations.

To detect the antianginal action of the compounds according to theinvention, investigations were carried out on mongrel days of both sexesunder pentobarbital anaesthesia (30 to 40 mg/kg i.v.) or underurethane/chloroalose anaesthesia (3 ml/kg urethane/chloralose mixturei.v.=20 mg/kg chloralose and 250 mg/kg urethane). The animals wereventilated with a bird mark 7 Respirator. The end-expiratory carbondioxide content (measured with an infrared absorption pen recorder) wasbetween 4.5 and 5% by vol. Throughout the experiment the animals underpentobarbital anaesthesia received a continuous infusion ofpentobarbital i.v.=4 mg (in 6 ml)/kg/h in order to ensure a constantdepth of anaesthesia. The animals under urethane/chloralose anaesthesiareceived no continuous infusion. The infusion was administered throughthe cephalic vein. After the experimental animals had been preparedabout 1 hour was allowed to elapse until all the haemodynamic parametershad reached a steady state. The actual experiment was then started.

To determine the mean peripheral blood pressure (=BP) the peripheralsystolic and diastolic blood pressure was measured in the femoral arteryusing a Statham pressure transducer. A Millar tip catheter advanced viathe carotid artery into the left ventricle provided the signal for theleft ventricular end-diastolic pressure (=LVEDP) and the heart rate(=HR).

The results obtained are shown in the table below.

    ______________________________________                                                Dose     BP       LVEDP   HR     DA                                   Substance                                                                             mg/kg    Δmm Hg                                                                           Δmm Hg                                                                          Δb/min                                                                         min                                  ______________________________________                                        A       0.3      -30      -3      +5     180                                  B       0.3      -25      -3      +5     180                                  C       0.3      -35      -4      +7     200                                  D       0.3      -25      -4.5    +4     180                                  E       0.3      -35      -4      +5     150                                  F       0.3      -40      -7      +8     150                                  Mol     0.1      -18      -2.3    +3      90                                  ______________________________________                                    

The meanings in the above table are as follows:

A=3-(2,6-Dimethylpiperidin-1-yl)-sydnonimine hydrochloride

B=3-(2,6-Dimethylpiperidin-1-yl)-N-benzoyl-sydnonimine

C=3-(2,6-Dimethylpiperidin-1-yl)-N-(allylthio)acetylsydnonimine

D=3-(2,6-Dimethylpiperidin-1-yl)-N-i-propoxycarbonylsydnonimine

E=3-(2,6-Dimethylpiperidin-1-yl)-N-butoxy-acetyl sydnonimine

F=3-(2,6-Dimethylpiperidin-1-yl)-sydnonimine hydrochloride

Mol=Comparison substance molsidomine(3-(morpholin-1-yl)-N-ethoxycarbonyl-sydnonimine)

BP=Mean peripheral blood pressure

LVEDP=Left ventricular end-diastolic pressure

HR=Heart rate (b/min=beats per minute)

DA=Duration of action

The preferred compounds of the formula I according to the invention are3-(2,6-dimethylpiperidin-1-yl)sydnonimine and the pharmacologicallyacceptable acid addition salts thereof, especially the hydrochloride, aswell as 3-(2,6-dimethylpiperidin-1-yl)-N-benzoyl-sydnonimine and3-(2,6-dimethylpiperidin-1-yl)-N-allylthiomethylcarbonyl-sydnonimine(=3-(2,6-dimethylpiperidin-1-yl)-N-(allylthio)-acetyl-sydnonimine) andthe acid addition salts thereof.

Unless otherwise indicated, the percentages indicated in the exampleswhich follow are percentages by weight. Ratios indicated betweencomponents of solvents or eluents are ratios by volume. Where given,m.p. denotes melting point and "decomp." denotes decomposition.

EXAMPLE 1 3-(2,6-dimethylpiperidin-1-yl)-sydnonimine hydrochloride

a) A solution of 13.4 g of sodium nitrite in 10 ml of water is addeddropwise to a mixture of 29.1 g ofN-(2,6-dimethylpiperidin-1-yl)-aminoacetonitrile, 100 ml of water, 100ml of ethyl acetate and 12 g of concentrated hydrochloric acid and,after stirring at room temperature for 5 hours, the organic phase isseparated off, diluted with 20 ml of methanol and stirred in an icebath. Hydrochloric acid is passed into saturation, and then the mixtureis stirred at room temperature for 15 hours and concentrated under waterpump vacuum. The residue crystallizes on trituration with diethyl ether.It is filtered off with suction and recrystallized from acetonitrile.

Yield: 18.2 g of 3-(2,6-dimethylpiperidin-1-yl)-sydnoniminehydrochloride

Melting point: 136°-137° C. (decomp.)

b) The starting material3-(2,6-dimethylpiperidin-1-yl)-aminoacetonitrile required above in a) isprepared as follows:

A solution of 11.5 g of sodium cyanide in 20 ml of water is added to amixture of 30.0 g of 1-amino-2,6-dimethylpiperidine, 20 g ofconcentrated hydrochloric acid and 100 ml of water cooled in ice, andthe pH is adjusted to 6.5 with hydrochloric acid. Then 19.3 g of a 39%strength aqueous formaldehyde solution are added, and the reactionmixture is stirred at 0° C. for 3 hours and at room temperature for afurther 3 hours. The product is extracted with ethyl acetate, and theethyl acetate phase is washed with dilute acetic acid and dried oversodium sulphate. Remaining after concentration is an oily residue (29.1g) which is, without further purification, further processed as in a).

EXAMPLE 2 3-(2,6-dimethylpiperidin-1-yl)-N-ethoxycarbonylsydnonimine

3.5 g of sodium bicarbonate are added to a solution of 5 g of3-(2,6-dimethylpiperidin-1-yl)-sydnonimine hydrochloride, prepared as inExample 1a), in 20 ml of water cooled in ice, and then a solution of 2.5g of ethyl chloroformate in 20 ml of methylene chloride is added, andthe mixture is stirred at room temperature for 4 hours. The organicphase is separated off, dried and concentrated. The residue istriturated with petroleum ether and filtered off with suction.

Yield: 4.2 g

Melting point: 90° to 91° C.

EXAMPLE 3 3-(3,5-Dimethylthiomorpholin-4-yl 1,1-dioxide)-sydnoniminehydrochloride

a) A mixture of 32.2 g of diallyl sulphone, 55 g of hydrazine hydrateand 54 ml of water is boiled for 30 minutes. The mixture is stirred inan ice bath, and the precipitate is filtered off with suction andrecrystallized from ethanol.

Yield: 16.2 g of 4-amino-3,5-dimethyl-thiomorpholine dioxide

Melting point: 181° to 183° C.

b) A mixture of 16.2 g of 4-amino-3,5-dimethylthiomorpholine dioxide,9.1 g of concentrated hydrochloric acid, 80 ml of water and 5.6 g ofsodium cyanide is cooled to 5° C. and 9.1 g of a 39% strengthformaldehyde solution are added (pH=7 to 7.5). The reaction mixture isthen stirred at room temperature for 4 hours. While cooling in ice themixture is acidified (pH=1), and a solution of 6.3 g of sodium nitritein 25 ml of water is added dropwise. The mixture is then stirred at roomtemperature for 3 hours, and the solid is filtered off with suction.

Yield: 16.0 g of N-(3,5-dimethylthiomorpholin-4-yl1,1-dioxide)-N-nitroso-aminoacetonitrile

Melting point: 163° to 165° C.

c) 15.8 g of N-(3,5-dimethylthiomorpholin-4-yl1,1-dioxide)-N-nitroso-aminoacetonitrile are dissolved in 100 ml ofmethanol and 100 ml of ethyl acetate and saturated with HCl. Theprecipitated solid is filtered off with suction, and the filtrate isconcentrated. The residue is triturated with absolute ethanol and withethyl acetate, filtered off with suction and dried.

Yield: 8.5 g of 3-(3,5-dimethylthiomorpholin-4-yl1,1-dioxide)-sydnonimine hydrochloride

Melting point: 192° C. (decomp.)

EXAMPLE 4 N-Ethoxycarbonyl-3-(3,5-dimethylthiomorpholin-4-yl)1,1-dioxide)-sydnonimine

3.9 g of sodium bicarbonate are added to a solution of 5.8 g of3-(3,5-dimethylthomorpholin-4-yl 1,1-dioxide)-sydnonimine hydrochloridein 20 ml of water cooled in ice, and then a solution of 3 g of ethylchloroformate in 20 ml of methylene chloride is added, and the mixtureis stirred in the ice bath for 6 hours. The organic phase is separatedoff, dried and concentrated. The residue is worked up by columnchromatography (silica gel, CH₂ Cl₂ :MeOH=97:3). The appropriatefractions are concentrated and the residue is triturated with diethylether and filtered off with suction.

Yield: 2.1 g

Melting point: 180° C. (decomp.)

EXAMPLE 5

N-Benzoyl-3-(2,6-dimethylpiperidin-1-yl)-sydnonimine is prepared inanalogy to Example 2 by reaction with 3.2 g of benzoyl chloride in placeof 2.5 g of ethyl chloroformate, and is recrystallized fromisopropanol/petroleum ether.

Yield: 3.4 g

Melting point: 141°-142° C.

EXAMPLE 6

N-Cyclohexylcarbonyl-3-(2,6-dimethylpiperidin-1-yl)-sydnoniminehydrochloride is prepared in analogy to Example 2 by use of 3.3 g ofcyclohexanecarbonyl chloride in place of 2.5 g of ethyl chloroformate.The oily base is dissolved in ethyl acetate and precipitated as the saltwith hydrogen chloride.

Yield: 3.8 g

Melting point: 111° C. (decomp.)

EXAMPLE 7

N-(Allylthio)-acetyl-3-(2,6-dimethylpiperidin-1-yl)-sydnoniminehydrochloride is prepared in analogy to Example 2 by use of 3.4 g of(allylthio)-acetyl chloride in place of 3.3 g of cyclohexanecarbonylchloride, and is precipitated from diisopropyl ether with hydrogenchloride.

Yield: 2.9 g

Melting point: 91° C. (decomp.)

EXAMPLE 8

N-n-Butoxy-acetyl-3-(2,6-dimethylpiperidin-1-yl)-sydnoniminehydrochloride is prepared in analogy to Example 2 by use of 3.4 g ofn-butoxy-acetyl chloride in place of allylthioacetyl chloride, and isprecipitated from diethyl ether with HCl.

Yield: 2.3 g

Melting point: 101° C. (decomp.)

EXAMPLE 9

N-Isopropoxycarbonyl-3-(2,6-dimethylpiperidin-1-yl)-sydnonimine isprepared in analogy to Example 2 (2.7 g of isopropyl chloroformate inplace of 2.5 g of ethyl chloroformate) and recrystallized from isopropylether.

Yield: 4.0 g

Melting point: 89°-90° C.

EXAMPLE 10

N-(2-Isopropoxy-ethoxy-carbonyl)-3-(2,6-dimethylpiperidin-1-yl)-sydnonimineis prepared in analogy to Example 2 (3.0 g of isopropoxyethylchloroformate in place of 2.5 g of ethyl chloroformate).

Yield: 4.5 g

Melting point: oil

EXAMPLE 11

N-(Imidazol-1-yl)-carbonyl)-3-(2,6-dimethylpiperidin-1-yl-sydnonimine.

A mixture of 3.7 g of 3-(2,6-dimethylpiperidin-1-yl)-sydnoniminehydrochloride, 2.4 g of carbonyl diimidazole, 2.5 g of sodiumbicarbonate and 50 ml of methylene chloride is stirred at roomtemperature for 16 hours. After removal of the solvent in vacuo, theresidue is taken up in 40 ml of 2N hydrochloric acid and extracted byshaking with diethyl ether. The aqueous phase is neutralized and thenthe product is extracted with diethyl ether, and the ether phase isdried and concentrated. The residue is recrystallized from isopropylether.

Yield: 2.8 g

Melting point: 119°-120° C.

EXAMPLE 12 3-(2,5-Dimethylpyrrolidin-1-yl)-sydnonimine hydrochloride

This compound is prepared in analogy to Example 1 starting from 11.4 gof N-(2,5-dimethylpyrrolidin-1-yl)-aminoacetonitrile and 7.6 g of sodiumnitrite.

Yield: 4.4 g

Melting point: 120° C. (decomp.)

EXAMPLE 13 N-Nitroso-3-(2,6-dimethylpiperidino)-sydnonimine

This compound is obtained by reaction of 3 g of3-(2,6-dimethylpiperidino)-sydnonimine hydrochloride with 0.93 g ofsodium nitrite in water, with addition of sufficient hydrochloric acidfor the pH to be between 2 and 3.

Yield: 2.1 g

Melting point: 74° C. (decomp.)

The compounds of the formula Ib indicated in the table which follows areprepared in analogy to Example 2.

    ______________________________________                                         ##STR11##                                                                    Nr.  A        R.sup.1               m.p. °C.                           ______________________________________                                        14   CH.sub.2 COCH.sub.3            115                                                                           (decomp.)                                 15   CH.sub.2 COCH(CH.sub.3).sub.2  131                                                                           (decomp.)                                 16   CH.sub.2                                                                                ##STR12##            128                                       17   CH.sub.2                                                                                ##STR13##             91 (decomp.)                             18   --                                                                                      ##STR14##            132                                       19   --                                                                                      ##STR15##            109                                       20   --                                                                                      ##STR16##            138                                       21   CH.sub.2                                                                                ##STR17##            129-131                                   22   CH.sub.2                                                                                ##STR18##            138 (decomp.)                             23   CH.sub.2                                                                                ##STR19##            118 (decomp.) (hydro- chloride)           24   CH.sub.2                                                                                ##STR20##            131-133                                   25   CH.sub.2                                                                                ##STR21##            101-102                                   26   CH.sub.2                                                                                ##STR22##             88-90                                    27   CH.sub.2                                                                                ##STR23##            149-151                                   28   CH.sub.2                                                                                ##STR24##             97-98                                    29   CH.sub.2                                                                                ##STR25##            117-118                                   30   CH.sub.2                                                                                ##STR26##            108-110                                   31   CH.sub.2                                                                                ##STR27##            120-121                                   32   CH.sub.2                                                                                ##STR28##             86-88                                    33   CH.sub.2                                                                                ##STR29##            149-152                                   34   CH.sub.2                                                                                ##STR30##             97-99 (decomp.) (hydro- chloride)        35   CH.sub.2 CO.sub.2 (CH.sub.2).sub.9CH.sub.3                                                                   104                                                                           (decomp.)                                                                     (hydro-                                                                       chloride)                                 36   CH.sub.2 CO.sub.2 (CH.sub.2).sub.17CH.sub.3                                                                   81                                                                           (decomp.)                                                                     (hydro-                                                                       chloride)                                 ______________________________________                                    

Where "-" is put for A in Examples 18 to 20 in the table, this means adirect bond, that is to say a 2,5-dimethylpyrrolidin-1-yl radical ispresent in the 3 position of the sydnonimine in Examples 18 to 20.

Pharmaceutical products are described in Examples A to F which follow.

EXAMPLE A Soft Gelatin Capsules Containing 5 mg of Active Substance PerCapsule

    ______________________________________                                                           per capsule                                                ______________________________________                                        Active substance      5 mg                                                    Triglyceride mixture fractionated                                             from coconut oil     150 mg                                                   Capsule content      155 mg                                                   ______________________________________                                    

EXAMPLE B Injectable Solution Containing 1 mg of Active Substance Per ml

    ______________________________________                                                              per ml                                                  ______________________________________                                        Active substance        1.0 mg                                                Polyethylene glycol 400 0.3 ml                                                Sodium chloride         2.7 mg                                                Water for injections    ad 1 ml                                               ______________________________________                                    

EXAMPLE C Emulsion Containing 3 mg of Active Substance Per 5 ml

    ______________________________________                                                           per 100 ml of emulsion                                     ______________________________________                                        Active substance     0.06 g                                                   Neutral oil          q.s.                                                     Sodium carboxymethylcellulose                                                                      0.6 g                                                    Polyoxyethylene stearate                                                                           q.s.                                                     Glycerol, pure       0.2 to 2.0 g                                             Flavouring           q.s.                                                     Water (deionized or distilled)                                                                     ad 100 ml                                                ______________________________________                                    

EXAMPLE D Rectal Drug Form Containing 4 mg of Active Substance PerSuppository

    ______________________________________                                                          per suppository                                             ______________________________________                                        Active substance    4 mg                                                      Suppository base    ad 2 g                                                    ______________________________________                                    

EXAMPLE E Tablets Containing 2 mg of Active Substance Per Tablet

    ______________________________________                                                           per tablet                                                 ______________________________________                                        Active substance      2 mg                                                    Maize starch         150 mg                                                   Lactose              60 mg                                                    Microcrystalline cellulose                                                                         50 mg                                                    Polyvinylpyrrolidone 20 mg                                                    Magnesium stearate    2 mg                                                    Sodium carboxymethyl starch                                                                        25 mg                                                                         309 mg                                                   ______________________________________                                    

EXAMPLE F Sugar-Coated Tablets Containing 1 mg of Active Substance PerTablet

    ______________________________________                                                         per tablet                                                   ______________________________________                                        Active substance   1 mg                                                       Maize starch       100 mg                                                     Lactose            60 mg                                                      sec. Calcium phosphate                                                                           30 mg                                                      Soluble starch     3 mg                                                       Magnesium stearate 2 mg                                                       Colloidal silica   4 mg                                                                          200 mg                                                     ______________________________________                                    

It is to be understood that the above described embodiments of theinvention are illustrative only, and that modifications thereof mayoccur to those skilled in the art. Accordingly, this invention is not tobe regarded as limited to the embodiments disclosed herein, but is to belimited only as defined by the appended claims.

We claim:
 1. Substituted 3-Aminisydonimines of the formula I ##STR31##and the pharmaceutically acceptable acid addition salts thereof, inwhich R¹ is selected from the group consisting of hydrogen and --COR⁴,R²is selected from the group consisting of alkyl having 1 to 4 C atoms andphenylalkyl having 1 to 4 C atoms in the alkyl radical, R⁴ is selectedfrom the group consisting of an aliphatic radical which has 1 to 6 Catoms and can also be substituted by alkoxy having 1 to 6 C atoms or byan aliphatic thio radical having up to 4 C atoms; a cycloaliphaticradical having 5 to 7 C atoms; an alkoxy radical which has 1 to 18 Catoms and can also be substituted by alkoxy having 1 to 6 C atoms; anaryl radical having 6 or 10 C atoms; an aryl radical which has 6 or 10atoms and is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkyl radicalshaving 1 to 4 C atoms and/or 1 or 3 alkoxy radicals having 1 to 4 Catoms and/or 1 or 2 alkyl- carbonyloxy radicals having 1 to 4 C atoms,and/or 1 to 3 alkylthio radicals having 1 to 4 C atoms and/or atri-fluoromethyl radical and/or an imidazole radical; an imidazolylradical; a pyridyl radical; a thienyl radical or a styryl radical. 2.Substituted 3-aminosydnonimines according to claim 1 characterized inthat R² methyl.
 3. A pharmaceutical product useful for controllingand/or preventing cardiovascular diseases and having, as activecomponent, from about 0.5 to 90 percent by weight of a compound of claim1 or of a pharmaceutically-acceptable acid-addition salt thereoftogether with a pharmaceutically-acceptable vehicle and, optionally, apharmaceutically-acceptable additive.
 4. A process for controlling orpreventing cardiovascular diseases which comprises administering aneffective amount of a pharmaceutically-active substituted3-aminosydnonimine of claim 1, or of a pharmaceutically-acceptableacid-addition salt thereof, to a host in need thereof.
 5. Substituted3-aminosydnonimines according to claim 1 characterized in that theradicals R² are in cis-position relative to one another. 6.3-(2,6-Dimethylpiperidin-1-yl)-sydnonimine and the pharmacologicallyacceptable acid addition salts thereof.
 7. A pharmaceutical productuseful for treating angina pectoris and/or high blood pressure andhaving, as active component, from about 0.5 to 90 percent by weight ofthe compound of claim 6 or of a pharmaceutically-acceptableacid-addition salt thereof together with a pharmaceutically-acceptablevehicle and, optionally, a pharmaceutically-acceptable additive.
 8. Aprocess for treating angina pectoris and/or high blood pressure whichcomprises administering an effective amount of the 3-aminosydnonimine ofclaim 6 or of a pharmaceutically-acceptable acid-addition salt thereof,to a host in need thereof. 9.3-(2,6-Dimethylpiperidin-1-yl)-N-(p-anisoyl) sydnonimine and thepharmacologically acceptable acid addition salts thereof.
 10. Apharmaceutical product useful for treating angina pectoris and/or highblood pressure and having, as active component, from about 0.5 to 90percent weight of the compound of claim 9 or of apharmaceutically-acceptable acid addition salt thereof together with apharmaceutically-acceptable vehicle and, optionally, apharmaceutically-acceptable additive.
 11. A process for treating anginapectoris and/or high blood pressure which comprises administering aneffective amount of the 3-aminosydnonimine of claim 9, or of apharmaceutically-acceptable acid-addition salt thereof, to a host inneed thereof.